Cancer is a group of diseases characterized by uncontrolled growth and dissemination of abnormal cells. It was estimated that in 2008 there were 12.7 million new cancer cases worldwide (Belcher E C-GK, Desantis C, Edwards B, Ferlay J, Forman D, Grey N, Harford J, Kramer J, McMikel A, McNeal B, O'Brien M, Pace L, Parkin M, Robbins A, Sankaranarayanan R, Sitas F, Slona R, Sullivan K, Wagner D, Ward E (2011) Global cancer facts and Figures, 2nd edn. American Cancer Society, Atlanta). For many patients afflicted with malignancies, chemotherapy offers the best options for disease control. Though chemotherapy is an effective way to treat many types of cancer, it also carries negative side effects. Patients treated with chemotherapy are at an increased risk of altered brain structure and function (de Ruiter M B, Reneman L, Boogerd W, Veltman D J, van Dam F S, Nederveen A J, Boven E, Schagen S B (2011) Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Hum Brain Mapp 32(8):1206-1219). Neurological abnormalities after chemotherapy might result from chemical neurotoxicity, indirect oxidative damage, inflammation or a type of autoimmune response. Clinical studies indicated that up to 70% of cancer patients who received chemotherapy experience cognitive impairment and other symptoms such as fatigue, anxiety and depression. This impairment, commonly named “chemobrain,” can affect working memory, attention, processing speed, concentration and executive functions (Christie L A, Acharya M M, Parihar V K, Nguyen A, Martirosian V, Limoli C L (2012) Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 18(7):1954-1965).
For most cancers, survival rates have improved over time, increasing the number of cancer survivors developing these cognitive symptoms (Myers J S (2009) Chemotherapy-related cognitive impairment. Clin J Oncol Nurs 13(4):413-421).
These side effects negatively impact their quality of life, impairing home, educational and occupational activities and unnecessarily extend disease-related disabilities (Harrington C B, Hansen J A, Moskowitz M, Todd B L, Feuerstein M (2010) It's not over when it's over: long-term symptoms in cancer survivors—a systematic review. Int J Psychiatry Med 40(2):163-181). In addition to cognitive deterioration, people treated with chemotherapy may have higher risk of developing depression due to physical suffering or as a complication of therapy itself. For example, long-term prophylaxis with tamoxifen, a selective estrogen receptor modulator commonly used for the hormone receptor-positive breast cancer, has been associated with a higher risk of developing depressive symptoms and cognitive dysfunction (Seliktar N, Polek C, Brooks A, Hardie T (2015) Cognition in breast cancer survivors: hormones versus depression. Psychooncology 24(4):402-407). Currently, there are no completely safe and effective treatments against these side effects (Joly F, Rigal O, Noal S, Giffard B (2011) Cognitive dysfunction and cancer: which consequences in terms of disease management? Psychooncology 20(12):1251-1258). Most memory enhancers currently available have significant side effects or limited efficacy in cancer patients. For example, donepezil, a pro-cholinergic drug, has been studied at the preclinical level, but the attempts to show efficacy in humans have been unsuccessful (Fardell J E, Vardy J, Johnston I N, Winocur G (2011) Chemotherapy and cognitive impairment: treatment options. Clin Pharmacol Ther 90(3):366-376).
One of the main concerns when selecting an antidepressant is the potential effect that the drug can have on the effectiveness or toxicity of the chemotherapeutic regime. For example, treatment of depression in a patient treated with tamoxifen can be complicated by drug interactions. Tamoxifen is a mainly inactive pro-drug, necessitating metabolism by the cytochrome P450 (CYP) pathway, into its active metabolites, 4-hydroxytamoxifen and endoxifen, to achieve its therapeutic effect. Some antidepressants such as the selective serotonin reuptake inhibitors (SSRI) paroxetine and fluoxetine affect the chemotherapy effectiveness by inhibiting the CYPD6 enzyme which metabolizes tamoxifen to its more active metabolites (Brauch H, Mürdter T E, Eichelbaum M, Schwab M (2009) Pharmacogenomics of tamoxifen therapy. Clin Chem 55(10):1770-1782).
Brain magnetic resonance imaging (MRI) analysis in patients treated with high-dose chemotherapy showed white matter lesions that correlated with greater neurocognitive decline (Fouladi M, Chintagumpala M, Laningham F H, Ashley D, Kellie S J, Langston J W, McCluggage C W, Woo S, Kocak M, Krull K, Kun L E, Mulhern R K, Gajjar A (2004) White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 22(22):4551-4560). Brain biopsies have shown signs of neurodegeneration and neuroinflammation induced by chemotherapeutic agents such as fragmented axonal fiber and minimally deprived myelination with many scattered macrophages (Choi S M, Lee S H, Yang Y S, Kim B C, Kim M K, Cho K H (2001) 5-fluorouracil-induced leukoencephalopathy in patients with breast cancer. J Korean Med Sci 16(3):328-334). A recent cross-sectional clinical study investigated the effects of adjuvant chemotherapy for breast cancer on the microstructure of cerebral white matter with magnetic resonance imaging (MM) (Koppelmans V, de Groot M, de Ruiter M B, Boogerd W, Seynaeve C, Vernooij M W, Niessen W J, Schagen S B, Breteler M M (2014) Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Hum Brain Mapp 35(3):889-899). The study found that among chemotherapy-exposed breast cancer survivors there was a fast deterioration of white matter microstructural integrity (Koppelmans V, de Groot M, de Ruiter M B, Boogerd W, Seynaeve C, Vernooij M W, Niessen W J, Schagen S B, Breteler M M (2014) Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy. Hum Brain Mapp 35(3):889-899). Even though the molecular mechanism(s) and effective therapeutic targets against brain injury induced by chemotherapy are largely unknown, this evidence suggests that chemotherapy induces brain injury and neuroinflammation and may cause the cognitive deficits and mood changes observed in cancer survivors.
However, to date there is no therapeutic agent to diminish cognitive impairment, anxiety, and depression after chemotherapy and long-term side effects associated with chemotherapy. Accordingly, there is not only a need in the art for therapeutic methodologies for increasing or enhancing neurogenesis in neurogenesis deficient individuals, including stress-induced neurogenesis deficits, increasing neurogenesis gene expression, and increasing neuronal cell formation, but also in the case of cancer patients undergoing systemic adjuvant chemotherapy, there is a need to treat the neuropsychological side effects of chemotherapy, such as cognitive impairment and depressive-like behavior induced by chemotherapy. Further, to date there are no methods in place to ameliorate neurogenesis deficits. Accordingly, there is a need in the art for therapeutic methodologies for increasing or enhancing neurogenesis in neurogenesis deficient individuals, including stress-induced neurogenesis deficits, increasing neurogenesis gene expression, and increasing neuronal cell formation.